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Targeting HORMAD1 splicing enhances MEK inhibitor sensitivity in breast cancers

Chenyan Sun1,2, Huacheng Luo1, Jing Zhang3,2

  • 1Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China.

RNA (New York, N.Y.)
|June 17, 2026
PubMed

Insights

BRCA1-mutant breast cancers develop resistance to PARP inhibitors. This study identifies a new vulnerability involving HORMAD1 regulation by RBM38, suggesting splicing modulation as a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in BRCA1 impair homologous recombination, driving breast cancer.
  • BRCA1-deficient tumors often develop resistance to PARP inhibitors, necessitating new therapeutic targets.
  • HORMAD1 overexpression in triple-negative breast cancer is linked to genomic instability, but its role in therapy response is unknown.

Purpose of the Study:

  • To investigate the role of HORMAD1 in BRCA1-mutant breast cancer therapy response.
  • To identify molecular vulnerabilities in BRCA1-deficient tumors resistant to standard treatments.
  • To explore the potential of targeting splicing regulation for enhancing treatment efficacy.

Main Methods:

  • Transcriptomic profiling of BRCA1-mutant breast cancer.
  • Treatment with splicing inhibitor Isoginkgetin.
  • Analysis of RNA-binding protein RBM38 and HORMAD1 splicing.
  • Assessment of MEK1 inhibition sensitivity after RBM38 knockdown.

Main Results:

  • HORMAD1 was identified as a highly upregulated and alternatively spliced gene in BRCA1-mutant breast cancer.
  • Isoginkgetin promoted HORMAD1 exon 4 inclusion, altering splicing patterns.
  • RBM38 knockdown sensitized BRCA1-mutant cells to MEK1 inhibition, highlighting an RBM38-HORMAD1 axis.
  • Splicing regulation emerged as a potential therapeutic vulnerability.

Conclusions:

  • The RBM38-HORMAD1 signaling pathway represents a potential therapeutic vulnerability in BRCA1-mutant breast cancer.
  • Targeting splicing regulation offers a promising strategy to overcome resistance and enhance treatment efficacy.
  • Further research into splicing modulation could lead to novel therapeutic approaches for breast cancer treatment.
Keywords:
BRCA1HORMAD1MEK inhibitorRBM38alternative splicing

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